Saturday, April 30, 2011

This past Tuesday, I attended a symposium on Music and the Brain. The subject is a fascinating one, and it is one that has been mentioned in part in this blog before.

There is a common mis-statement of *lateralization* of brain function. Popular science and psychology magazines promote the concept that analytic functions are confined to the left hemisphere of the brain, and artistic functions (including music) are confined to the right hemisphere. While there is *some* lateralization, the statement is so simplistic as to be false. However, when it comes to speech, there is a clear concentration of neural function in Broca's area to in the left frontal lobe - it is not exclusive, and the right side can take over function in the event of damage. That was one of the main subjects of the symposium - use of music: melody and rhythm to restore speech in patients with stroke or head injury that damages the brain regions involved in speech.

Interestingly, humming and singing does *not* involve the same part of the brain as speech. Patients with "aphasia" are unable to speak some or all words (even though the same patient can read or write those same words) can hum or even sing those same words! By capitalizing on this remaining brain function, Dr. Gottfried Schlaug of Beth Israel Deaconess Medical Center and Harvard University is using melody and rhythm to restore speech in patients with damage to speech centers.

The "arcuate fasciculus," shown above, appears to play a major role in speech, but more importantly in music. The fasciculus is mistakenly cited as connecting Wernicke's with Broca's areas. But as can be seen, it extends much further, connecting most of the Temporal Lobe with the Frontal Lobe - including, but not limited to, the language (Wernicke's) and speech (Broca's) centers.

Next up was a fascinating talk using MRI and PET imaging techniques to look at active regions of the brain during music performance, conducting, listening and even imagining. Dr. Donald Hodges of UNC Greensboro revealed some surprises - for example, a professional musician actually has *lower* activity in the frontal lobe when performing. While the exact reason is not precisely known, the researchers and musicians agree that excessive *thinking* is counterproductive to a trained musician, and the reduce frontal activity could be a means of "getting the brain out of the way."

Other amazing findings come from scans of music conductors - whether playing, conducting or just *imagining* a musical performance, professional musicians activate a *lot* of the brain - motor areas, auditory areas, the "melody circuit" (arcuate fasciculus), visual areas, cerebellum and many other areas involved in processing music. These findings were confirmed by Dr. Jonathan Burdette of Wake Forest Medical School, who described the networks of brain areas involved in music perception and performance. One of the important conclusions is that music is *not* lateralized to just one half of the brain! Nor is the center for processing music confined to just one area. Music activates a wide network of neurons through all of the brain, left, right, front, back, top, bottom - and may turn out to be one of the most fundamental networks of the human cognitive function.

I regret that I could not attend the final talk, in which Dr. Patricia Gray of UNCG spoke of finding brain networks in Great Apes that respond to rhythm and essential elements of music. It is a fascinating study that shows that while melody generation exists in some lower species (i.e. birdsong) - the concept of *music* is a function of the cognitive functioning of the higher primates.

All in all a fascinating series of lectures, and reinforcement that the human brain is a strange and wonderful thing.

So, until next time, take care of your brain - and feed it some music!

Friday, April 29, 2011

The diagram at right shows the general process of neuron-to-neuron signaling by neurotransmitters - chemical signaling agents produced by neurons, released by neurons, acting on neurons, and degraded by or in the vicinity of neurons. This general scheme is true for the "catecholamines" (norepinephrine, dopamine, serotonin) and GABA. Acetylcholine differs in that the molecule is first split into acetyl and choline halves before before taken up by the transmitting neuron.

The action of a neurotransmitter at a synapse is limited by (A) how much neurotransmitter reaches the receptors, (B) how quickly it is taken back up by the neurons, and (C) how quickly it is broken down. There are a number of ways to subvert this system - block the receptors, block the reuptake transporter, block the metabolic enzymes, etc. Many plant and animal toxins block the receptors. Insecticides and nerve agents block the metabolic enzymes, anesthetics block the receptors and/or the transporters, and chemicals similar in structure to neurotransmitters can mimic the normal chemical and interfere with any or all three processes.

This brings us to the subject of "Good Neurotransmitters Gone Bad..."

The chemical structures above show several of the neurotransmitters (circled) introduced in the previous blog, and the major psychoactive drugs that interfere with them. Note that each category of abused drugs correspond to one or more natural neurotransmitter drugs (except one, and we will get to that later). In each case, there is some similarity in chemical formula - or more importantly, 3-D chemical shape - between the abused drug and the neurotransmitter. This allows the abused drug to mimic the neurotransmitter at the receptor, or interfere with the reuptake transporters and/or metabolic enzymes (usually because they are not *guite* the same shape/formula) and thereby increasing the amount of time that the neurotransmitter is present in the synapse.

Note also that with the Narcotics, we introduce another neurotransmitter - enkephalin - which is present mostly in the spinal cord (but also in brain) to modulate the sensation of pain.

Then there's that lonely little THC molecule down in the lower left. Tetrahydrocannabinol is the main psychoactive ingredient in marijuana. For years it was thought to act either at the same receptors as narcotics, or by changing the neuron membrane. The external membrane of any cell is a lipid (wax or oil). "Floating" in the lipid are the proteins which give a cell its shape, and in neurons, the proteins which serve as ion channels, receptors and transporters. The long "tail" on THC indicates that it *can* dissolve in lipids and have an effect by changing how easily the proteins move around in the lipid. However, for the last 20 years we've known that there are specific receptors that respond specifically to the "cannabinoid" drugs. Fifteen years ago the first "endogenous" or naturally occurring cannabinoid-like chemicals were identified in the brain, and about 10 years ago we discovered what those chemicals do. We know that THC and the cannabinoids have the potential to affect *all* of the other neurotransmitters, because the natural chemicals can change how much neurotransmitter is released on a moment-by-moment basis.

So, the secret to *why* abused drugs have an effect, is that they look like the normal brain chemicals. The issue of *how* they have an effect depends on what the normal role of the neurotransmitter is: Norepinephrine is involved in attention => amphetamine is a stimulant; Dopamine is involved in risk/reward circuits => cocaine produces an extreme pleasurable "rush"; Serotonin is involved in sleep, dreaming and modulating sensory information => LSD causes hallucinations; GABA is the main inhibitor in the brain => ethanol relaxes and eventually depresses neuron activity; enkaphalin modulates pain = > heroin reduces pain to the point of producing euphoria. There are many more drugs that could be mentioned, but most fall into these main categories, and the common feature is interference with natural neurotransmitter function.

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Next up, two Weekend Special posts, then back to the Guide with "What's the Code" on Monday, May 2. Until next time, beware of imitation neurotransmitters - because they might just be a good drug gone bad.

Thursday, April 28, 2011

Very sorry not to have a post here tonight. It's about half written, and the next one is even ready to post, but is out of sequence.

This is one of those cases in which it is revealed that Speaker to Lab Animals is, in fact, a real professor. My excuse for missing the scheduled blog post is that I am doing the final reading of a Master's Thesis prior to a student's Thesis Defense tomorrow morning.

My apologies for missing the deadline, and I will have a part 2 of "You Think You've Got Chemistry..." up tomorrow for certain.

Tuesday, April 26, 2011

Welcome to the "Function" section of The Lab Rats Guide to the Brain. The first post in this section is actually the post on Oxygen and Glucose utilization that I posted about a month ago (http://teddysratlab.blogspot.com/2011/03/give-me-air.html). We will start with some recap some previous discussions about neurotransmitters and then look further into the chemistry of the brain.

Like all of the other cells of the body, the brain rests in a salt-water solution. When popular scientific articles use this fact as evidence of evolution from sea-life, they often make a huge mis-statement about that salty solution - usually in claiming that the salinity of blood, lymph and cerebrospinal fluid is the same as seawater.

It isn't.

Seawater on average ranges from 2 to 4% salt, and is often higher in concentration in some of the "brackish" wetlands that are home to many transitional creatures. The saline solution in the body is a pretty precise 0.9% salt. Even salt-water fish do not have much higher than 1% salt in their body fluids, the gills only allow water through into the blood and intracellular fluids - salt is concentrated and excreted, much like what our kidneys do.

Yet the salt solution in our bodies has some very specific functions: in the kidneys, regions with different concentrations of salt (ranging from 1-2%) serve the important purpose of helping to retain and conserve water and keep the body from being dehydrated (or losing too many chemicals in the urine). In the brain, the compounds comprising the salts (mostly sodium-, potassium-, calcium-, and magnesium- as -chlorides, -sulfates and -carbonates) are separated, resulting in charged molecules (ions) that can be used to form electrical and chemical gradients (above, right). This separation of ionic charge allows voltage to be built up, then discharge when channels that pass these ions are selectively opened (left).Any separation, then selective discharge of electrical charge can be harnessed to do *work* as the physicists term it. In the case of the brain, the "work" is the transfer of information from neuron to neuron as a pattern of electrical pulses.

So, on the one hand, the chemistry of the brain is one of electrolytes and electrical currents. Then there are the chemical neurotransmitters that act in place of a "spark" jumping from neuron to neuron.

However, if all neurons had the exact same chemistry, there would be no way to make different neurons do different jobs. After all, if all neurons were simple on-off switches, the brain would be a *Very* dumb switching station. Even a digital computer relies on different voltages, and transistors which have some very exotic properties other than a simple on-off.

The brain has a much more complex circuitry - there are excitatory neurons, inhibitory neurons, neurons which switch roles depending their targets. To allow the *same* basic unit - a neuron - to perform wildly different functions, the brain - and nervous system in general - uses different neurotransmitters to connect neurons. In fact, a single neuron will quite frequently have receptors for most of the common neurotransmitters (at right) so that inputs from different brain areas have different functions. While most neurons will only *make and release* one of the neurotransmitters, they can respond to any neurotransmitter for which they have the appropriate "receptor". The neurotransmitter and receptor act as a sort of "lock and key" system, where the receptor on a neuron is the lock, and the key is the neurotransmitter chemical. Only if the appropriate neurotransmitter "key" is present, will the receptor "unlock" and perform the appropriate action on the neuron. In addition, there can be different receptors that recognize different parts of the chemical, and have different actions on the neuron (such as excitation vs. inhibition).

With all of that chemical activity, is it any wonder than the chemicals we ingest (eat, drink, sniff, smoke, inject or smear on the skin) can have such a profound effect on brain function? In the next blog we will look at the different ways that externally applied drugs appear similar in structure to neurotransmitters in order to alter brain function.

So stay tuned for "You Think You've Got Chemistry? Part 2" the day after tomorrow.

Sunday, April 24, 2011

I know I'm scheduled to start "From Brain to Mind" today, but I found one more entry in the mailbag that's worth answering:

"Dr. Roberts: What is a spinal tap?"

Oh, yeah, that's a really good question. To explain, let me start back in the brain. As with all tissues in the body, the brain has an extensive supply of blood vessels, however, there is a very tight wall made of specialized cells lining the blood vessels allowing only water and certain chemicals through the the spaces around the neurons. To cushion and bathe the neurons, the brain floats in a fluid called "Cerebrospinal Fluid" (CSF), which consists of the fluid which filters out of the blood and is generated inside 4 spaces within the brain called "ventricles". The figure at right shows these spaces (the two lateral ventricles are also labeled as the first and second ventricles). At the base of the cerebellum, the ventricles also connect to the space outside the brain that cushions between brain and skull. There is a tough tissue lining the inside of the skull (dura), and another tightly conforming to the surface of the brain (pia). The space between is filled with CSF and the combination of inner and outer lining plus CSF is quite commonly known as "meninges" - and is the root of the disease name "meningitis" (and inflammation of the tissue lining and increased fluid pressure due to bacterial or viral infection).

You will notice that below the fourth ventricle the space narrows. The cross section at left shows the continuation of this tube as the "central canal" down through the middle of the spinal cord. The central canal is continuous with the ventricles of the brain, forming a complete internal system draining fluid and chemicals from the brain. Likewise, the external space - the meninges - continue down along the outside of the spinal cord.

The fact that these spaces are continuous means that anything that appears in the CSF in the brain will eventually appear in the CSF of the spinal cord. Evidence of infection, inflammation, or neural damage will result in an increase in certain proteins and neurotransmitter chemicals in the CSF. Since flow of the CSF is from inside to outside, the best place to sample the CSF is from either the fourth ventricle or the central canal.of the spinal cord.

This is where the spinal tap comes in. Doctors can insert a long, hair-thin needle into the spinal cord and withdraw a small amount of CSF for analysis. Since the spinal cord is encased in bone (right), the needle has to be threaded between the vertebrae, into the spinal cord and right to the central canal. It's a bit tricky, but there are guiding features that allow the needle to be inserted in the proper place. In fact, the indentations that separate the left and right sides of the spinal cord (above) ensure that the needle is directed to the center, and do not enter the neuron- and axon-packed regions to either side.

One of the problems with spinal tap is the "spinal headache" that often follows. Injection sites don't necessarily completely seal up, and CSF can leak out into the meninges, the decrease in pressure throughout the central canal and ventricles, coupled to the increase in fluid in the "epidural" space between pia and dura, causes headaches until the injection site completely seals - either by clotting or scar formation. These days there are newer analysis techniques based on MRI that are replacing the need for spinal tap in many cases, but there are also very good reasons to directly sample the fluid in closest contact with the brain.

There is another reason to enter this space - injection of a very small amount of anesthetic (spinal block) allows surgeons to cut all muscle movement and tactile/pain sensation to a specif region of the body by targeting only that region where the appropriate nerves enter and exit the spinal cord. On a larger scale, infusion of anesthetic into the space inside the dura, surrounding the spinal cord (epidural), will block pain sensation to all body regions below the injection point.

And for those who have wondered, the spinal tap needle isn't *really* a foot long, it just seems that way. It's about 4 inches, and is so fine that you really don't feel it enter the skin or the spinal cord. What you feel is the pressure and the slight CSF loss that accompanies the needle entry. It's really not something to be worried or scared of, but it is becoming increasingly rare in this age of digital imaging and analyses.

Many thanks to my readers who send in such great questions!

Tune in next time for the next installment in The Lab Rats' Guide to the Brain: From Brain to Mind.

Entitled "Brains Aflame", it's a great article on some of the same stuff I've been talking about here. It also triggered a brief discussion on Baen's Bar about the tendency of brains to operate on *symbols* rather than raw data. A perfect memory would be one in which every single detail is preserved - a so-called "photographic memory" is an example. However, storing raw data is inefficient, storing symbols and association is much more efficient.

I have spoken before about the fact that memory storage is (A) distributed across many brain areas and hundreds if not thousands of synapses between neurons, and (B) associative - linked to other concepts and memories. If each synapse stored a tiny detail, it would not be possible to retrieve the entire memory using the "addresses" of just a few synapses. Instead, memory is stored as symbols that are linked to each other. In one of my studies I found neurons that responded to *categories* of images - such as color vs. black and white, line art vs. photographs, etc., thus minor details could change, and the neurons would still respond to the various feature categories in the image(s) to be remembered. By linking categories or features, and associating them with other mnemonic details, it is possible to store a lot of information, make it highly redundant, and retrieve it using only a few associated details.

The process of learning and using symbols is developed as the brain transitions from infancy to adulthood. Likewise, the dependence on raw data lessens, and "photographic memory" capability diminishes. If, in the case of savants, the ability to process and store all of the raw data is retained throughout development, there is a corresponding impairment in the ability to process symbols, leading to many of the autism-like characteristics of the savant.

Back to the subject of the linked article - it features a discussion of networks in the brain and how they can be studied. I think this audience would enjoy the diversion, and I thank Baen Books and Publisher Toni Weisskopf for featuring science on the website.

Next week we dig into the section of the Lab Rats' Guide to the Brain that I have entitled "From Brain to Mind" featuring a discussion of brain function including:

Wednesday, April 20, 2011

All the LabRats are dancing, there's questions in the mailbag! Well, most of the LabRats are dancing - Ratface is just sort of wobbling around and Nestor got tangled up in the electrical cord for the disco ball!

OK, Ratley, bring over that heavy mailbag.

[squeak]

What do you mean there's only one?

[squeak]

Oh, well, even one will do. Hand it here, please.

[squeak]

What?!? Oh, well - [sounds of brushing, sweeping, vacuuming, washing, rinsing, more sweeping...]
Sorry about that, YDR* (*YouDirtyRat) seemed to think the mailbag was a laundry bag. Now that I can actually see the handwriting, let me see what we have here...
Hmm...
Um... yeah...
Yes... good one.

Okay, S.C. is a writer and wants to know what signs and markers might be present if an alien technology caused a person to develop heretofore unknown mental abilities. She asks if there are proteins, other markers, and any way to find out other than by spinal tap (shudders).

[SQUEAK!]

Yes, Ratley, S.C. already figured out that there would be headaches.

[squeak]

That's okay, and yes, the question has a real application, and scientists do know how to look for changes in the brain. Tell you what, Ratley, you give the answer while I get Ratface unstuck from the letter slot...

[Squeak, squeak, squee, squick, squee-eeek!]

Translation...

Thanks, Doc!

Okay, S.C. you mentioned thinking of something similar to what happens when muscles develop, and that's a good analogy. See, we actually know a lot about what happens when a human - or LabRat - learns something new.

First, there is a principle that was first published by Donald Hebb in 1949. We call it "Hebb's Rule" and it states that for any neuron that is active - that is firing off action potentials (the "lightning" as Speaker likes to call it) - if the inputs to that neuron become active, then the synapses - connections between the neurons will become stronger. Think of an input and an output. If they are both active, then the connection between them gets stronger. If you have a way to make *sure* that both are active, then you "teach" the synapse to become more active under that condition.

We now know that this is really an oversimplified idea, and it doesn't always work this way, but it is a pretty good description of a mechanism we call "plasticity" and is an important part of learning and memory. In particular, making new connections is how memory is stored, but it's also the way baby brains develop into adult brains, and how brains recover and rehabilitate after injury. The key feature is that the synapses - the connection between the axon of one neuron and the dendrite or soma of its target neuron - are changed: they become bigger, there are more receptors for the chemical neurotransmitters, there is more neurotransmitter synthesized, the gap becomes smaller, and the connection with the rest of the neuron becomes larger.

And we can detect that.

First off, there are gene changes. Proteins are being made. We can see those by sampling some cells, grinding them up and doing some lab bench work.

Yeah, icky, and worse than a spinal tap. Trust me, on that.

Well, we see more electrical activity. You can get that by putting a wire recording electrode next to the neurons, but some signs are visible in the EEG recorded from the scalp.

The process requires oxygen, and oxygen requires blood flow. We can track that in a number of ways, but the most important is a technique the docs call "functional magnetic resonance imaging." Those big old MRI machines can actually find which brain areas are using the most oxygen and superimpose that on a picture of the brain. In 3-D, and you don't even need those awful glasses.

The process also requires glucose, and there's good ways to track that, too - Positron Emission Tomography - used in clinics to look for cancer and in labs to study brain activity. PET as it is called, would be a good way to look for anything abnormal going on.

Thanks, Ratley! Now that Ratface is out of trouble - for the next 2 minutes - I'll mention something that Ratley probably didn't realize - the really smart guys who develop new MRI techniques have figured out a way to use it for spectroscopic analysis. Those proteins and factors that we formerly needed to "grind and bind" the cells to study? Well, maybe not for long. MR spectroscopy has a lot of promise to being able to track different types of chemical activity.

So, SC - the short answer is that we could look for many of these signs of *plasticity* and they'd give a suggestion that something new was happening in the brain - and we won't necessarily need a spinal tap to do it! Of course the splitting migraines and headaches and fainting for no apparently reason would tell us that *something* was happening, but these techniques could give us a better idea of what and where.

Thanks for asking, thanks for reading, and remember folks, questions from the readers are always welcome. Besides, the LabRats so seldom get a chance to dance, with their cute little formal gowns and tuxedoes...

I mean scientific misstatements - not to simplify the science, not to fit the plot - but inaccurate science simply because the producers/writers or consumers/viewers/readers don't bother to check the facts and get it right.

My son had a Physics class where the teacher ranted on about Stupid Movie Science in the form of cars that explode at the slightest impact, guns that never run out of bullets, explosions in space, objects falling more than 30 feet and landing unharmed.

[For clarification: cars seldom explode. They *burn* but explosions are very rare. Most guns can hold 10-30 bullets, even without fully automatic fire, it can take less than a minute to shoot them all. Space is a vacuum, there is no sound, no flame, and no smoke. The acceleration of gravity is 32 feet per second. By the time an object falls 32 feet, it will have been falling for *more* than a second, since the average speed is 1/2 the acceleration, and will therefore experience a deceleration equivalent to more than 1 gravity - in addition to the normal 1 gravity experienced at rest. 48 feet and the stopping force is 2 G's, 70 feet and it's 30 G's, etc. That's a pretty hard shock.]

It can be argued that Stupid Movie Science persists because the *consumers* don't know any better. That may be true, but then the burden is on teachers to educate their students to eliminate ignorance.

But for brain science it is even worse. The general population doesn't understand the brain, it is not part of the basic science curriculum in schools. Thus we have several of my "favorite" examples of bad TV and movie brain science:

Star Trek: The Original Series, episode "Spock's Brain." The Vulcan's brain is removed and put in a computer. Doctor McCoy brings Spock's body along, using only a little handheld remote and some Lego's on Spock's forehead to control the body. Kirk outwits the computer (of course), they rescue Spock's brain, and McCoy has to put it back in the body - with Spock's help once he "reconnects the vocal cords."
Do I need to go into all of the reasons why this is ridiculous? Can I just leave it at the fact that McCoy would have to have been nearly done with surgery (attaching 12 cranial nerves, spinal cord, eyes, ears, etc. before Spock could speak?

Star Trek: The Next Generation - just about any episode where Dr. Crusher opened her mouth to speak. My favorite examples: "The engram has wrapped itself around his cerebellar cortex!" or any time she mentions hippocampus. It's wrong, wrong, wrong. Engrams are patterns, not physical entities that can "wrap themselves" around anything. Besides, she was pointing to the *cerebrum*, not the cerebellum!

The Matrix. OMG. The brain connection probes would leave no room for *brain* inside the skull! There was a time when middle school and high school biology students did experiments with the leg muscle of frogs. To prepare the frog, it was necessary to "pith" them - disconnect the brain, but leave the spinal cord and reflexes intact. The technique required putting a steel probe that was *smaller* (in relative size to human brain) than the Matrix probe into the base of the brain, thus destroying the neuron connections between brain and spinal cord. I *cannot* watch the Matrix without thinking of pithed frogs.

Any movie or TV show with "brain bugs"... yeah.... No. Sorry, the brain is very sensitive, and as stated before with the Matrix, and intrusion into the skull is going to do a lot of damage. A bug, worm or snake crawling around in there? Nope, that victim will be comatose and brain dead *very* quickly.

Any military adventure or SF book that postulates "combat drugs" and refers to them containing "methamphetamine" when they *really* mean amphetamine. [Yes, John Ringo, I'm looking at you!]. It's true, methamphetamine was initially developed as a more potent, hopefully less addicting alternative to amphetamine. Didn't work, and althought the military had some trials with the drug 20+ years ago, those were abandoned. There are much more effective (and safer) alternatives.

Soap opera - total amnesia. You know the scene, subject sustains a blow to the head (usually the top or back) and has total amnesia. 20 years later they sustain another blow and wake up with a 20 year gap and a whole second life. No. No. and Hell, No! First, the location of the blow to the head is usually wrong (top and back produces sensory damage, forehead or temple area and most associated with amnesia. Second, total retrograde amnesia (memory of past events) is rare, and when it does occur, lasts only hours or days. *Anterograde* amnesia - loss of memory of the accident, and a few hours either direction - is more common with a head injury. Fugue states lasting 20 years are a sign of seriously messed up neurochemicals or deep rooted psychological problems, a blow to the head is not going to trigger it.

Saturday, April 16, 2011

[Sorry for anyone that might get this blog twice... I had to edit and repost to test an email feature...]

We finish the "Parts of the Brain" portion of The Lab Rats' Guide to the Brain by examining the one brain part that does not occupy the same space as the "brain." In other words, the spinal cord is more properly considered an extension of the brain, than simply a conduit for nerves to reach the parts of the brain.

On the other hand, that is precisely what the spinal cord does - provide a tract for ascending (sensory) and descending (motor) neurons to send their axons to the respective targets (brain and muscles). The correspondence with level of the spinal cord and the region it connects ("innervates" is the term used by neuroscientists and physicians) is fairly obvious for the major limbs - i.e. arms are innervated by axons that enter/exit the spinal cord at the neck and shoulder level; legs are innervated by axons that enter/exit at the lumbar, or lower back level. However, what may not be as obvious is the correspondence of the nerves serving internal organs. The chart at right shows the origin of the axons entering and leaving the spinal cord (in particular the ganglia that run parallel to the spinal cord) with different levels of the "spinal column" (spinal cord, vertebrae plus all associated nerves entering, exiting and running parallel to the spine). The internal organs usually cannot be sensed by themselves, which is why internal pain is often associated with the nearest "peripheral" nerves, i.e. heart with arms, stomach with chest, kidneys with lower back.

The statement above about ganglia, however is very important - axons do not travel all the way between brain and muscle or organ. Sensory nerves send projections to the spinal cord, where the axons form synapses on neuron cell bodies *in* the spinal cord, which then send *their* axons to the brain (typically to the thalamus). Motor neuron axons descending from the brain likewise form synapses with neurons with cell bodies either in the spinal cord or in the spinal ganglia (parallel to the spinal cord). Those neurons then project their axons to the various muscles and organs.

The diagram above shows a cross-section of the spinal cord. The central "circle" is the spinal cord. It is divided in half, just like the brain, to serve the symmetrical halves of the body. At 4 o'clock and 8 o'clock positions are the projections from brain to body - called the anterior or "ventral roots". Axons are from neurons in the spinal cord that project to the muscles and organs. The posterior or "dorsal roots" at the 10 and 2 o'clock positions are neurons entering the spinal cord. These "roots" contain a swelliing or "ganglia" that contain the cell bodies for neurons connecting the sensory receptors to the spinal cord. The dorsal and ventral roots comprise the spinal nerves, and project out between the vertebrae, or bones of the spine. [A "pinched nerve" or "slipped disk" results in unusual pressure on the spinal nerves, damaging the neurons, producing pain and possibly altering muscle movement.] The dark shaded "butterfly" in the center of the spinal cord is Gray Matter, consisting of the cell bodies of the neurons which serve each level of the spinal column. The lighter shading is White Matter and consists of the axons ascending and descending in well defined columns serving each part of the body.

At the right is a series of sections through the spinal cord at different levels - C.VIII or C8 is in the lower cervical (neck) area. TH.VI or T6 is in the thoracic, or mid-back area. L.I - Lumbar or L1 - is in the lower back, while S.I - Sacral or S1 - is just above the tailbone or sacrum. The size of the section shows the relative diameter of the spinal cord at each level. C8 and L1 have a greater diameter than T6 and S1 because the major nerve connections to the arms are C6-8 and for the legs at L1-4. Note also that there is very little white matter in S.1, due to the fact that most of the axons enter and exit the spinal cord *above* the S1 level. Likewise, while T6 has a smaller diameter than L1, it has more white matter, since it includes the axons for all body regions served below T6 - including those from L1.

Thus the spinal cord acts as a mediary between muscle/sensory systems and brain. This is in fact a very important function, in that many of the *reflex* actions are controlled solely by the spinal cord. The sensation of extreme cold or heat on the hand, followed by a reflex withdrawal of the hand from the heat/cold source is a reflex. Some reflex still exists when the spinal cord is severed and does not require the brain to function. Every muscle used to *extend* a limb, whether arm, leg, finger, etc. is counterbalanced by a *flexor* which produces opposite, bending motion. If *both* muscles were active at the same time, our limbs would be rigid, unable to move. Neurons in each muscle and in the tendons where muscles attach to bone sense the stretch and contraction of muscles. Neurons in the spinal cord alter the signals to the *opposing* muscle group to tell the muscles to stop resiting the motion. There *is* conscious control of the reflex. Once a target muscle position is achieved, other signals from brain (cerebellum and basal ganglia) turn the opposing muscles back on so enable a smooth stop with no overshoot, oscillation or tremor. Again, the connections are made in the spinal cord and, and result in the enlarged Gray Matter regions in the spinal cord at the major input/output points for those muscle systems.

In this manner, the spinal cord is in essence an extension of the brain - or at least the brainstem, thalamus and basal ganglia - down into the remainder of the body. It is well armored by the vertebrae of the spine, and cushioned by cerebrospinal fluid (in the subarachnoid space), just like the brain. Sampling and analyzing the cerebrospinal fluid at the level of the spinal cord (i.e. a spinal tap) can tell doctors many things about the functioning of the nervous system. Delivery of drugs directly to the spinal cord can effectively anesthetize *only* the parts of the body connected to that specific region of the spinal cord (epidural or spinal anesthesia).

At the same time, the spinal cord is easily damaged, and we will cover aspects of spinal cord damage, paralysis, paresis and chronic pain when The Lab Rats' Guide to the Brain moves on to the section on diseases and disorders of the brain.

On that note, this is the final blog post on parts of the brain. There will be a brief recess - one or two blogs - before starting the next section. This would be a good time for mailbag questions, some miscellaneous musings on science and fiction, and perhaps time to exercise the LabRats.

So please, send in questions, fill out the poll in the upper right, recommend this blog to your friends ... and take care of your spinal cord - it has a way of telling you when you don't!

Thursday, April 14, 2011

I'm introducing a new term this post - "Ganglion" - line "nucleus" this denotes a grouping of neurons, in particular, a compact mass of neuron cell bodies. In brain terms, "ganglion" is used interchangeably with "nucleus", although the term "ganglion" has additional meanings in the general body.

The Basal Ganglia (or Basal Nuclei) are structures that are located at the base of the brain, above and to the side of the thalamus. From this, one might think that the Basal Ganglia develop as part of the diencephalon, like the thalamus and hypothlamaus, but that is not true. The Basal Ganglia are part of the telencephalon, and developmentally are part of the same formation as the cerebral cortex which forms the "higher" functions of the brain. So, what are they, and what so they do?

The Basal Ganglia consist of four main structures: Striatum - so called because of the striped pattern in cross-section due to the projections from thalamus to cortex that pass through the striatum; Globus Pallidus (pallidum) - the "Pale Globe"; Substantia Nigra - named for the darkly-pigmented dopamine-producing neurons; and the Subthalamic Nucleus. Striatum consists of a dorsal (top) portion termed the Caudate Nucleus, the middle segment is termed Putamen, and the ventral (bottom) portion contains Nucleus Accumbens. The latter is frequently associated with a Limbic System circuit which includes the Ventral Pallidum and a mesencephalon structure: the Ventral Tegmental Area - this is important, and will be discussed later.

In the brain slice above, the "holes" in the center are the ventricles - they collect and filter thecerebrospinal fluid with cushions the brain and drains waste chemicals from the brain. The dark masses twoard the center and below the ventricles comprise the basal ganglia. The white streaks in the Striatum are the axons of the neurons connecting Thalamus (which is behind this slice) and the cortex (dark gray margin lining the surface and folds of the brain). The gray regions are indeed "Gray Matter" and consist mainly of neuron cell bodies. The white areas are "White Matter" and consist mostly of axons - they have a waxy coating called "Myelin" which produces the white color.

The major role of the Basal Ganglia is one of inhibition. The majority of BG neurons utilize the neurotransmitter GABA (gamma-aminobyutyric acid - blue arrows in diagram at right) which has a suppressive or inhibitory effect at the synapses of targeted neurons. GABA neurons in Striatum project to GABA neurons in Globus Pallidus (GPe, GPi) and Substantia Nigra (SNr). GABA neurons in those locations project in turn to thalamus or cortex. The Pallidal neurons are constantly active, producing a continuous inhibition on their targets. When the inhibitory Striatum inputs to Pallidum are activated, the inhibition turns *off* the inhibition by Pallidum - a phenomenon called "disinhibition." Since the Thalamus feeds back to the Cortex to regulate muscle movement, the net result is to inhibit the inhibition of Thalamus, and produce hyperactivity of motor movements. However, there is balance in the circuit (right). The Subthalamic Nucleus (STN) neurons are excitatory (red arrows) and cause a net inhibition of the Thalamus resulting in hypoactivity of motor movements. This is contradictory, but balanced by dopamine neurons in Substantia Nigra (SNc) which modulate the Striatum, balancing the inhibitory and excitatory effects of motor neurons.

...and this can lead to problems. Parkinson's Disease results in loss of the Dopamine neurons in Substantia Nigra, causing the Basal Ganglia to "stick" in one state or the other, leading to tremors (hyperactivity) or extreme rigidity and difficulty initiating movements (hypoactivity). There are numerous movement-related disorders associated with damage to or misfunction of the Basal Ganglia (Cerebral Palsy, Huntington's Disease, Parkinson's, Chorea, twitches, tics, etc.). Other diseases, syndromes and disorders include Attention Deficit/Hyperactivity Disorder, Tourette's Syndrome, and Obsessive Compulsive Disorder.

This leads to the second major role of BG - motivation. Parkinson's patients have difficulty *motivating* their bodies to move, but there are other aspects of motivation as well. The Limbic Basal Ganglia - Nucleus Accumbens (NA), Ventral Pallidum (VP) and Ventral Tegmental Area (VTA) are involved in emotional and risk-reward associated motivation as well. NA and VP act similar to Striatum and GP with inhibitory projections in this role, with VTA acting in the Substantia Nigra role to provide Dopamine producing neurons.
This latter circuit is particularly important in behavior and memory research, because it has been shown to be involved in individual judgment of reward, resulting in the willingness of a subject to perform behavioral tasks and receive a reward or reinforcement for that behavior.

In Science Fiction, this circuit has been immortalized as the "Brain Reward Circuit." Author Larry Niven wrote of patients with electrodes in their brain that would choose electrically-generated pleasure over any other type of reward. Likewise Spider Robinson included a similar "addiction" in some of his stories. In current neuropsychological research, the limbic Basal Ganglia are associated with drug abuse due to the fact that Dopamine levels are easily altered by cocaine, amphetamine, methamphetamine and other drugs.

However, in the interest of time and space, these matters will be discussed in a later blog as we cover various brain diseases and disorders. Next up we will close the section on parts of the brain with a discussion of the one part that is not considered physically part of the brain: the spinal cord.

Tuesday, April 12, 2011

In popular culture, it is fairly common knowledge that there is a portion of the nervous system dedicated to the “Fight or Flight” response.We call it the “Sympathetic Nervous System” and it largely consists of a chain of ganglia (clusters of neuron cell bodies) that run parallel to the spinal cord and have origins in the brainstem and thalamus to prepare the body for activity by increasing heart rate, breathing, tighten muscles, dilate pupils and nostrils and flood the bloodstream with adrenaline.

A similar system, the “Parasympathetic Nervous System” serves the functions of “Feed and Breed” and is responsible for hunger, satiety, body temperature, and hormonal control of the body.The origins of the latter are in the hypothalamus, which acts as the brain’s major control interface with many separate systems of the body.

The diagram at the right shows a slightly expanded illustration of the different nuclei of the hypothalamus. You can see from the diagram that hypothalamus lies under the thalamus (hence the name). It also lies just forward of thalamus and brainstem (mesencephalon) and in the center of the brain - compared to the thalamus that forms the base of the two lateral hemispheres of the brain. This is not to say that the hypothalamus doesn't have right/left divisions. The picture below left shows the same structures from a 90 degree rotated angle (the thalamus is outlined in yellow). [By the way, the beautiful Frank Netter diagram above was first commissioned by CIBA pharmaceuticals in the 1930's. Netter is the acknowledged foremost medical illustrator, and his diagrams are considered *the* standard in medical textbooks.]

One of the characteristics of many neurons in the hypothalamus is that instead of releasing their neurotransmitters directly onto other neurons, they release into the blood. At this stage, the chemicals are termed "neuromodulators" because they act to alter neuron activity, instead of directly causing inhibition or excitation of a neuron. The more familiar name is "hormone. The blob hanging down from the middle of the hypothalamus above is the pituitary gland. It is most familiar for it's role in promoting adrenaline release from the adrenals glands sitting on top of the kidneys. However, it has other functions as well, as will be detailed below.

Pituitary - while technically a gland, and therefore not a nucleus of the hypothalamus, the pituitary (or "Hypophysis" in Neurogeek-speak) is the site at which many of the neuromodulators produced in hypothalamus get into the blood.

There are two divisions - Anterior, also known as "Adenohypophysis" (named for its effect on glands) makes and secretes:

Adrenocorticotropic Hormone (ACTH) which stimulates the adrenal gland. ACTH release is stimulated by CRH from the Paraventricular Nucleus)

The Posterior pituitary stores and releases oxytocin (responsible for labor during pregnancy) and vasopressin. The latter, also known as "Antidiuretic Hormone" regulates blood pressure directly through action on the muscle that line the arteries, but also by regulating water retention in the kidneys.

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So, that's a lot of functions. If the Thalamus is the controller for neuron signals, hypothalamus is the controller for chemical signals. Together with the basal ganglia (next topic) they form the "diencephalon" which is essentially the *core* of the brain, and is the bare minimum structures necessary for most of what we think of as the essential functions of the brain apart from conscious thought.

Not bad for something about the size of a walnut. Kind of makes you rethink those prejudices against dinosaurs, right?

Until next time, "Take care of your Brain, it's the only one you've got!"

Sunday, April 10, 2011

Welcome any new readers that may be coming here from the Ravencon science fiction convention in Richmond, VA this past weekend. Thanks for coming, and I invite you to browse the archives to look over the content for "The Lab Rats' Guide to the Brain" and other miscellaneous posts inspired by "nerdy science" (neuroscience). There are two good starting points in the archives: Thursday, Feb. 3 titled "Brain and Brain, what is Brain" begins the discussion of the essential building blocks of the brain. Sunday, Feb. 20 titled "Back to Basics" introduces the section we are currently completing on parts of the brain.

There are three entries left in the brain structure for us to cover: hypothalamus, basal ganglia and the spinal cord. We will be resuming that discussion in the next post. If you are new to the blog, *please* go back and browse through the archives for information on areas and regions of the brain, their essential functions, and *some* detail of diseases and disorders.

After completing the discussion of brain structure, we will move on to brain function as revealed by diseases and disorders. We have discussed a few cases, and I will probably reiterate a few in the appropriate context. Section 4 of the guide, to commence later this Spring will examine "Brain Cliches", those examples of "Stupid Movie Science" (and TV and print) that drive viewers crazy and spread misinformation and confusion about brain science.

A key discussion from this past weekend was the importance of content tags and labels. I will be relabeling some of the older posts to facilitate search engines. Thus some of you may come to this blog via search engines - I will try to develop an introductory section and table of contents for future use and organize the Guide into eventual print form.

Interspersed with Guide blogs are personal observation of science, science fiction and travel. After completion of the Guide, there will be some room to repeat and revise sections as I prepare it for eventual submission to a publisher, and I am considering a series which explores some aspects of science in established science fiction novels, TV and movies - often in a tongue-in-cheek manner. I am planning blogs essentially three days per week, although the current posting schedule of every even date - (i.e. 2nd, 4th, 6th, etc of each month) allows for one extra blog every two weeks. Content will typically be two Lab Rats' Guide to the Brain posts interspersed with one or two posts of related content. The occasional diversion will be clearly indicated (like today) and will still have an aspect of science, life and speculation (with bonus short fiction!).

To wrap up, I'd like to mention something I heard at Ravencon (credit to novelist John Ringo and journalist Kelly Lockhart): Back in the 60's, the U.S. space program managed to design build and fly a rocket to the moon despite the fact that many people - including the designers and builders - felt that the job was impossible. The effort took an increadible feat of science and engineering. It succeeded because people believed in it. There is a theory (by novelist and physicist Travis Taylor, Ph.D.) that human brains are connected at the quantum level, and that as such, belief can truly affect outcomes in the physical world. I am not entirely sure that I believe the theory, but then, I am a neurophysiologist/pharmacologist, and not a quantum physicist. In fact, I would love to discuss the issue with Dr. Taylor at some point in the future - perhaps in this space. Nevertheless, I do believe as a society that when we truly *believed* in science, we made science happen. I despair that our current society may no longer truly believe - but it is my goal to explain, and thereby bolster the belief and understand of brain science in a manner that the writers (and blog readers) of today can shape the minds of tomorrow and restore that belief.

Friday, April 8, 2011

We have covered many functions of the thalamus in the prior sections. Rather than repeat the descriptions, this blog will instead simply provide a diagram and list of components (and functions) of the thalamus:

Wednesday, April 6, 2011

Oh, I don't mean like "Hey Dr. Johnson! You've won the Nobel Prize! What're you going to do next?" followed by the response "I'm going to Walt Disney World!"

No, I mean in the time travel stories. No one ever seems to ask the scientists what they would do with a Time Machine. Sure, the historians want to go back and observe some key moment in history. Politicians talk about changing a key political moment (I'll just satisfy Godwin's Law right here and mention all of the stories that revolve around stopping Hitler). Ask an English major and they may wish to see an original Shakespeare play, a sport's fan will want to replace that critical last game in the championship.

But no one seems to ask the scientists.

Would a zoologist want to take that ocean voyage on the Beagle with Darwin? A physicist give Stephen Hawking a vaccine to prevent ALS? A microbiologist visit von Leeuwenhook as he put the drop of pond water under his microscope?

Or would someone *please* go back and tell Carl von Linne to stop with all the latin-sounding names for his taxonomy system (while you're at it, tell him that he doesn't need a "mineral" kingdom for living organisms - at least not until the computers take over).

For myself, I've been thinking of the eminent neurosurgeon Wilder Penfield, and how I wouldn't mind standing at his elbow with a modern low-noise amplifier, digital oscilloscope and precision stimulator. So much of what we now know in neuroscience derived from very crude experiments performed in the process of doing or treating something else. If Penfield had access to better epilepsy drugs, he would never have performed the experiments that led to identification of function throughout the brain. Without his initial experiments, 80 years worth of neuroscience would not have resulted in our current body of knowledge.

Modern epilepsy drugs would have saved the famous patient "H.M." from surgical removal of his medial temporal lobes, preventing the anterograde amnesia that plagued the rest of his life. But perhaps in that case, we would know and understand little about the hippocampus' role in memory.

It is true that in any field, we stand on the backs of giants, but we also stand on accidents, mistakes, and the failures of our own lack of knowledge or development. Who knows? Perhaps a healthy Hawking would have been a rock star, and the thwarted Herr Schicklgruber a better painter. Maybe it's better if we *don't* really know who wrote the plays attributed to William Shakespeare?

Monday, April 4, 2011

In the last blog I showed the diagram at right - which purports to be the cerebellum and brainstem.

Yet, the diagram below comes from Gray's Anatomy:

I've blown it up to show the fine detail with which Gray describes the various parts of the brainstem - and how it appears to include many more structures than the simple diagram favored by most illustrators.

In the lettered, color diagram, A is the midbrain (portions of thalamus and hypothalamus); B is the pons, C is the medulla, and D is the top of the spinal cord. Gray's diagram doesn't pay much attention to the medulla and spinal cord, but does show an important feature which is the exit points of many of the cranial nerves - the ones serving many of the primary sensory inputs and essential controls for face, throat, heart, lungs, diaphragm, etc.

The medulla is the site of many of the "automatic" functions for the body - sweat glands, heart rate, blood pressure, respiration. Spinal cord is obviously the conduit for neuron connections between brain and body, but it serves as so much more - damage to the spinal cord alone will leave a patient paralyzed, but still alive - damage to medulla may require that the patient be on total life support - with pacemaker, respirator, and a central line to deliver nutrients. Damage *above* the medulla will leave the body intact, heart beating, breathing, muscle reflexes intact - just with no higher brain function.

The pons is the location where many of the nerve fibers cross-over to the opposite side such that the right side of the body is connected to the left side of the brain, and vice versa. The bulge in B actually results from the crossing fibers.

Above the medula and pons termed "mesencephalon" (middle brain), is the beginning of "brain" proper with the "diencephalon" (inter-brain). The diagram at right compares the human brain with that of a shark. The major developmental change leading to *higher* brain development is in the "telencephalon" (top brain). The diencephalon includes the thalamus, hypothalamus, and the many structures associated with thalamus that act as relays for the sensory and motor regions of the brain. As seen in Gray's diagram, this includes the colliculi and geniculate bodies.

The "primitive" brain of the shark includes all of the functions for controlling the body. As long as the diencephalon and lower structures are intact, the body is fully function - what then makes the difference in the human brain? More sensory detail, more more detail, all of the association cortices - and conscious control of all of the above. The need for memory storage also contributes to enlargement of the telencephalon.

So the brainstem is more than just a vestigial piece of spinal cord sticking out of the bottom of the brain. Rather, the brainstem is the *original* brain - designed for control of reflexes, and automatic (the technical term is "autonomic") processes. We will talk further about the "Control Center" aspects of the diencephalon when we discuss Hypothalamus in the next blog post.

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Administrative note: Blog posts for the forseeable future will return to a 3-4 per week schedule. Unfortunately, last week's glitch threw me off of the "every even date" plan, although I will strive to return to that schedule by mid-month.